Macroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved intracellular degradation mechanism involved in diverse biological activities and in the pathogenesis of many diseases. The homeostatic importance of autophagy for the liver is indicated in the fact that autophagy deficiency causes multiple liver pathologies, including hepatomegaly, injury, inflammation, ductular reaction, fibrosis and tumorigenesis. What are being triggered by autophagy deficiency to lead to these changes are largely unknown but understanding the involved mechanisms will provide the insight not only on how autophagy maintains hepatic homeostasis, but also on how similar processes occur in other chronic diseases, such as those caused by alcohol, hyper-nutrients, and hepatic viruses. Toward that end, we have found that HMGB1 is actively released from autophagy-deficient hepatocytes, which is different from the more commonly seen case of passive release from dead cells during injury, but is similar to the active release by macrophages during inflammation. Regulatory mechanisms including Nrf2 and Caspase1 affect HMGB1 release independently from liver injury. HMGB1 acts in an extracellular mode and requires its receptor, RAGE, to regulate the ductular reaction, i.e., the expansion of ductular cells (DRs), also known as hepatic progenitor cells (HPCs) or oval cells, and to promote the development of hepatic tumors. These results indicate that hepatic HMGB1 plays an important and unique role in the liver pathogenesis caused by autophagy deficiency. The proposal have three aims. In Aim 1 we will investigate the mechanism of HMGB1 release from hepatocytes, addressing the hypothesis that inflammasomes are involved in the process. In Aim 2 we will examine the mechanism of ductular reaction promoted by HMGB1. In Aim 3 we will dissect the mechanisms of HMGB1 in tumor progression by examining the hypothesis that HMGB1 may alter the hepatic microenvironment. The successful completion of this work will reveal the novel roles of hepatocyte-derived HMGB1 in hepatic homeostasis and the results may be generally applicable to similar pathogenic processes in other types of chronic liver diseases, thus advancing the research in this field.